Invasive breast carcinoma is a group of malignant epithelial tumors characterized by invasion of adjacent tissues and a marked tendency to metastasize to distant sites. Breast cancer exhibits a wide range of morphological phenotypes and specific histopathological types that have particular prognostic and clinical characteristics. For example, subtypes are stratified according to their estrogen receptor (ER), progesterone receptor (PR) and human epidural growth factor receptor (HER2) status. For many patients, targeted therapies against one of the receptor targets are available. However, 10-20% of mammary tumors lack hormone receptors (ER/PR) and do not overexpress Her2/neu protein, clinically defined as triple negative breast cancer.
Triple negative breast cancers are more aggressive than ER/PR+ tumors or Her2+ tumors, and there are no targeted therapies available for this disease. The use of an anthracycline, taxane, and an alkylating agent is recommended. However, a large number of patients treated with chemotherapy and surgery for early breast cancer (EBC) are not cured of their disease. Approximately 30% to 40% of patients with TNBC will have a recurrence of disease within 3 to 10 years of treatment with neoadjuvant therapy and surgery. Most patients with recurrent disease will die from their breast cancer. Therefore, identification of therapeutic advances is critical.
Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that recognizes DNA damage and facilitates DNA repair. PARP activity is required for the repair of single-stranded DNA breaks through the base excision repair pathways. Cancer cells are often deficient in double-stranded DNA-repair capability, and are therefore more dependent on PARP directed single-stranded DNA-repair than are normal cells. Consequently, inhibition of PARP enhances the anti-tumor effects of DNA-damaging agents in many cancer cells.
Most early breast cancers are treated with multi-modality therapy (surgery+/−radiotherapy+chemotherapy). Multiple large randomized trials have demonstrated identical outcomes may be obtained irrespective of the order of surgery and chemotherapy. Thus neoadjuvant (chemotherapy followed by surgery) and adjuvant (surgery followed by chemotherapy) treatment regimens are considered equivalent. One advantage of neoadjuvant therapy is that tumor responses to chemotherapy can be measured, unlike in the adjuvant setting where all known tumor is surgically removed prior to chemotherapy. The tumor response to neoadjuvant chemotherapy provides significant prognostic information. Those patients that achieve complete pathological tumor responses (no living cancer cells can be identified in the surgical specimen) have significantly better prognoses than those that do not.
It has been discovered that the PARP inhibitor veliparib, 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, acts synergistically in combination with the DNA-damaging agent carboplatin to increase the efficacy of the current standard-of-care treatment for early triple negative breast cancer. Adding veliparib and carboplatin to the standard of care increases the number of women that achieve pCR status in a neoadjuvant setting. This is estimated to translate into additional treated women remaining free of disease at 5 years. This is also expected increase the number of patients who would become eligible for less extensive surgery (fewer mastectomies, more breast-conserving surgery).